Omeprazole, an alkaline salt thereof, the (-)-enantiomer of omeprazole and an alkaline salt of the (-)-enantiomer of omeprazole, all compounds hereinafter referred to as omeprazole, are used in the treatment of gastric acid related diseases. Omeprazole and pharmaceutically acceptable salts thereof are described in EP 5129, and some specific alkaline salts of omeprazole are described in EP 124 495 and WO95/01977. Certain salts of the single enantiomers of omeprazole and their preparation are described in WO94/27988.
Omeprazole is generally known to be useful for inhibiting gastric acid secretion in mammals and man by controlling gastric acid secretion at the final step of the acid secretory pathway. Thus, in a more general sense, it may be used for prevention and treatment of gastric-acid related diseases in mammals and man, including e.g. reflux oesophagitis, gastritis, duodenitis, gastric ulcers and duodenal ulcers. Furthermore, it may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with non ulcer dyspepsia, in patients with symptomatic gastro-oesophageal reflux disease, and in patients with gastrinomas. It may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre-and postoperatively to prevent aspiration of gastric acid and to prevent and treat stress ulceration. Further, it may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these, as well as in the treatment or prophylaxis of inflammatory conditions in mammals, including man.
Omeprazole is, however, susceptible to degradation or transformation in acidic and neutral media. The degradation is catalyzed by acidic compounds and is stabilized in mixtures with alkaline compounds. The stability of omeprazole is also affected by moisture, heat, organic solvents and to some degree by light.
With respect to the stability properties of omeprazole, it is obvious that an oral solid dosage form must be protected from contact with the acidic gastric juice and that omeprazole must be transferred in intact form to that part of the gastrointestinal tract where pH is near neutral and where rapid absorption can occur.
A pharmaceutical oral dosage form of omeprazole is best protected from contact with acidic gastric juice by an enteric coating layer. In EP 247 983 such an enteric coated formulation of omeprazole is described. The formulation contains omeprazole in the form of a core unit containing omeprazole together with an alkaline salt or containing an alkaline salt of omeprazole optionally together with an alkaline salt, the core unit is layered with a separating layer and an enteric coating layer. In WO 96/01623 a multiple unit tableted dosage formulation of omeprazole is described.
The oral formulations described in EP 247 983 and the tablet formulations decribed in WO 96/01623 are enteric coating layered formulations which comprise or may comprise a separating layer to separate the acidic enteric coating material from omeprazole being an acid susceptible substance. HPMC of low viscosity may be used as a binding agent in the core material or as a layer separating the core material from the enteric coating layer in the described formulations. All ingredients, including HPMC qualities, used in a pharmaceutical preparations must fulfill strict criteria, such as for instance requirements defined in pharmacopoeial monographs.
The rate of release of omeprazole from a pharmaceutical dosage form can influence the total extent of absorption of omeprazole into the general circulation (Pilbrant and Cederberg, Scand. J. Gastroenterology 1985; 20 (suppl. 108) p. 113-120). Therefore the limits for rate of release of the omeprazole from the pharmaceutical formulation are stated in the marketing approval for the products.
It has now surprisingly been found that different batches of low viscosity HPMC, which fulfill all pharmacopoeial requirements, used as binder in the formation of omeprazole containing cores or as material for the separating layer of enteric coating layered formulations of omeprazole, may differ with respect to their ability of influensing the rate of release of omeprazole in simulated intestinal fluid, USP, in vitro. One parameter of interest in the release rate influensing ability of the HPMC is its water solublity.
The aqueous solubility of HPMC decreases with increasing temperature due to polymer phase separation. This is observed as a clouding of the polymer solution when the temperature is increased. Cloud point is the temperature at which this polymer phase separation occurs. Cloud point is determined by measuring the light transmission through the polymer solution. The light transmission of a specific system where the polymer is dissolved, that is a transparent polymer solution without clouding, is defined as light transmission 100%. In this patent application cloud point is defined as the temperature where the light transmission of a specific system is 96% when a commercial instrument from Mettler is used. For other cloud point systems and instruments another light transmission may be specified for each system.
One problem which can be avoided by the new formulation and use of a specific quality of HPMC is that the amount of product discard can be reduced. From an economical aspect it is advantageous to specify and check the HPMC quality and keep the discard of produced pharmaceutical product low.